Dosage and administration of anti-EGFR therapeutics

ABSTRACT

Methods for optimizing a therapeutic response in a patient (e.g., a cancer patient) to an anti-EGFR therapy, and methods for preventing or ameliorating infusion reactions in a patient receiving an anti-EGFR therapy are disclosed.

CROSS REFERENCE TO RELATED APPLICATIONS

This application is a continuation of International Application No.PCT/US2015/030870, filed on May 14, 2015, which claims priority to, andthe benefit of, U.S. Application No. 61/996819, filed on May 14, 2014,and U.S. Application No. 62/005401, filed on May 30, 2014. The contentsof the aforementioned applications are hereby incorporated by referencein their entireties.

SEQUENCE LISTING

The instant application contains a Sequence Listing which has beensubmitted electronically in ASCII format and is hereby incorporated byreference in its entirety. Said ASCII copy, created on Sep. 28, 2015, isnamed MMJ-046PCCN_SL.txt and is 9,916 bytes in size.

BACKGROUND

Appropriate dosing of parenteral medications such as antibodypreparations is a critical factor in their administration to patients.One aspect of the requirement for safe and effective dosing schemes isthat infusion reactions are occasionally associated with administrationof antibody preparations to patients. In the field of anticancertherapy, infusion reactions have been reported in association with theadministration of several antibody-targeted therapeutics, includingrituximab, trastuzumab, bevacizumab, cetuximab and panitumumab. Suchinfusion reactions include chills, pyrexia and dizziness, which areoften associated with hypersensitivity and allergic symptoms such asurticaria. Severe infusion reactions may be life-threatening and includeanaphylactoid symptoms such as dyspnea, bronchospasm, hypotension, lossof consciousness and shock, or even myocardial infarction or cardiacarrest in some patients. Infusion related reactions are assigned gradesaccording to the National Cancer Institute Common Terminology Criteriafor Adverse Events (Version 4.0) as follows. Grade 1 includes a mildtransient reaction, wherein interruption of infusion and/orinterventions is not indicated. Grade 2 includes reactions that indicatethe therapy or infusion should be interrupted, but the reaction respondspromptly to symptomatic treatment (e.g., NSAIDS, narcotics, orintravenous (i.v.) fluids). In such cases, prophylactic medications areindicated for up to 24 hours at the discretion of the physician orstaff. Grade 3 reactions include prolonged infusion related reactions(e.g., reactions not rapidly responsive to symptomatic medication and/ora brief interruption of infusion), a recurrence of symptoms followinginitial improvement, and hospitalization indicated for clinicalsequelae. Grade 4 includes infusion related reactions withlife-threatening consequences, and urgent intervention indicated as wellas cessation of infusion. Grade 5 includes infusion related reactionscausing the death of the patient.

Anti-EGFR antibodies provide beneficial therapy for various cancers, butmay be ineffective or lose effectiveness over time. Newer EGFRinhibitory antibody preparations are in development, includingoligoclonal mixtures of anti-EGFR monoclonal antibodies. Oligoclonalanti-EGFR antibody mixtures represent a recent advance in anti-EGFRcancer therapy and have been shown preclinically to provide superioranti-cancer therapeutic effects. MM-151 and Sym004 are oligoclonalmixtures of antibodies that bind to the extracellular domain of EGFR andinhibit EGFR activity. MM-151 comprises a formulation in apharmaceutically acceptable carrier of a triple combination ofmonoclonal antibody P1X, monoclonal antibody P2X, and monoclonalantibody P3X at a P1X:P2X:P3X molar ratio of 2:2:1. These experimentaltherapies are designed to be more potent than first generation anti-EGFRmonoclonal antibodies, and thus require specially adapted dosing andadministration schedules and procedures.

Thus, there is an unmet need to develop and implement methods of safelyand effectively administering novel antibody-comprising therapeutics,including methods for preventing and ameliorating infusion reactions inpatients, e.g., cancer patients receiving such therapeutics. Thefollowing disclosure provides such methods and confers additionaladvantages.

SUMMARY

Disclosed herein are compositions and methods designed to safely andeffectively administer oligoclonal anti-EGFR antibody preparations suchas MM-151 and Sym004 and to prevent and ameliorate infusion reactions inpatients receiving treatment such antibody-based therapeutics.

In one aspect, a method is provided for treating a cancer in a humanpatient by administering an oligoclonal mixture of anti-EGFR antibodiesto the patient, wherein the method comprises intravenously administeringthe oligoclonal mixture of anti-EGFR antibodies in at least onetreatment cycle, the at least one cycle comprising:

an initial two week treatment cycle consisting of a first week and asecond week, wherein a first dose of the an oligoclonal mixture ofanti-EGFR antibodies is administered during the first week administeredat a rate of X mg/hour for a first ½ hour, immediately followed by arate of 2X mg/hour for a second ½ hour, immediately followed by a rateof 4X mg/hour until all of the first dose has been administered and asecond dose, that is greater than or equal to the first dose, isadministered during the second week; wherein administration, at eachrate subsequent to the first ½ hour, is optionally one or more of:delayed, altered or not carried out if the patient exhibits an adversereaction to the administration at the preceding rate. In one embodiment,if the patient exhibits an adverse reaction to the administration of theanti-EGFR antibodies at the preceding rate (i.e., the rate at which theadverse reaction was observed) and the alteration comprises aninterruption of administration, i) the patient is treated for symptomsof the adverse reaction at the discretion of an attending clinician, andii) following treatment of the symptoms, the administration is resumedat a rate lower than or equal to the rate at which the administrationwas interrupted. In one embodiment, the administration is resumed athalf the rate at which the administration was interrupted.

In another formulation of this aspect, provided herein is use of anoligoclonal mixture of anti-EGFR antibodies (for the manufacture of amedicament) for treating a cancer in a human patient by intravenousadministration of the medicament to the patient in at least onetreatment cycle, the at least one cycle comprising: an initial two weektreatment cycle consisting of a first week and a second week, wherein afirst dose of the an oligoclonal mixture of anti-EGFR antibodies isadministered during the first week administered at a rate of X mg/hourfor a first ½ hour, immediately followed by a rate of 2X mg/hour for asecond ½ hour, immediately followed by a rate of 4X mg/hour until all ofthe first dose has been administered and a second dose, that is greaterthan or equal to the first dose, is administered during the second week.

In one embodiment, the second dose is administered at a rate of Xmg/hour for a first ½ hour, immediately followed by a rate of 2X mg/hourfor a second ½ hour, immediately followed by a rate of 4X mg/hour for athird ½ hour, immediately followed by a rate of 8X mg/hour until all ofthe second dose has been administered, wherein administration at eachrate of the second dose is optionally either delayed or not carried outif the patient exhibits an adverse reaction to the administration at thepreceding rate or of the preceding dose.

In another embodiment, if the patient tolerates the initial cycle, theat least one cycle further comprises at least one subsequent treatmentcycle, each treatment cycle comprising at least one administration ofthe oligoclonal mixture of anti-EGFR antibodies at a third dose. Inanother embodiment, the third dose is greater than or equal to thesecond dose and is greater than the first dose.

In another embodiment, if the third dose of the oligoclonal mixture ofanti-EGFR antibodies is administered, it is administered at a rate of 2Xmg/hour for a first ½ hour, immediately followed by a rate of 4X mg/hourfor a second ½ hour, immediately followed by a rate of 8X mg/hour for athird ½ hour, immediately followed by a rate of 16X mg/hour until all ofthe third dose has been administered. In one embodiment, X is 25.

In one embodiment, the first dose of the oligoclonal mixture ofanti-EGFR antibodies is about 225 mg or is about 3 mg/kg. In anotherembodiment, the second dose is about 450 mg or is about 6 mg/kg.

In one embodiment, the at least one subsequent treatment cycle is threeweeks or four weeks.

In another embodiment, the at least one subsequent treatment cycle isfour weeks, and, if administered, the third dose is administered on day1 of each week of the four week treatment cycle. In yet anotherembodiment, the at least one subsequent treatment cycle is four weeks,and, if administered, the third dose is administered during the firstweek and the third week of each four week cycle.

In one embodiment, the at least one subsequent treatment cycle is threeweeks, and, if administered, the third dose of the oligoclonal mixtureof anti-EGFR antibodies is administered during week 1 of each three weekcycle. In another embodiment, the oligoclonal mixture of anti-EGFRantibodies consists of two or more anti-EGFR antibodies.

In one embodiment, the oligoclonal mixture of anti-EGFR antibodiesconsists of anti-EGFR antibodies that specifically bind to two or moredifferent epitopes of the extracellular domain of EGFR.

In one embodiment, the two or more different epitopes is three differentepitopes.

In one embodiment, the two or more anti-EGFR antibodies is threeanti-EGFR antibodies. In another embodiment, the three anti-EGFRantibodies is MM-151bio or optionally MM-151. In yet another embodiment,the three anti-EGFR antibodies comprise a first antibody with a heavychain comprising SEQ ID NO:1 and a light chain comprising SEQ ID NO:2; asecond antibody with a heavy chain comprising SEQ ID NO:3 and a lightchain comprising SEQ ID NO:4; and a third antibody with a heavy chaincomprising SEQ ID NO:5 and a light chain comprising SEQ ID NO:6. Inanother embodiment, the three anti-EGFR antibodies comprise a firstantibody comprising heavy chain CDRs 1, 2 and 3 set forth in SEQ ID NOs:7, 8 and 9 respectively, and light chain CDRs 1, 2 and 3 set forth inSEQ ID NOs: 10, 11 and 12 respectively; a second antibody comprisingheavy chain CDRs 1, 2 and 3 set forth in SEQ ID NOs: 13, 14 and 15respectively, and light chain CDRs 1, 2 and 3 set forth in SEQ ID NOs:16, 17, and 18 respectively; and a third antibody comprising heavy chainCDRs 1, 2 and 3 set forth in SEQ ID NOs: 19, 20 and 21 respectively, andlight chain CDRs 1, 2 and 3 set forth in SEQ ID NOs: 22, 23 and 24respectively.

In another embodiment, the antibodies are IgG antibodies, optionallyIgG1 antibodies.

In another embodiment, the third dose (and optionally each subsequentdose) of the oligoclonal mixture of anti-EGFR antibodies is about 4.5mg/kg, about 6 mg/kg, about 7.5 mg/kg, about 9 mg/kg, about 10 mg/kg,about 10.5 mg/kg, about 11 mg/kg, about 12 mg/kg, about 13 mg/kg, about14 mg/kg, about 15 mg/kg, about 18 mg/kg, or about 20 mg/kg, and isadministered weekly, bi-weekly or tri-weekly. In one embodiment, thethird dose of the oligoclonal mixture of anti-EGFR antibodies is 10.5mg/kg. In one embodiment, the 10.5 mg/kg is administered weekly.

In another aspect, provided are methods for treating a patient having acancer, comprising co-administration of a topoisomerase inhibitor andthe oligoclonal mixture of anti-EGFR antibodies. In one embodiment, theat least one dose of a topoisomerase inhibitor is administered at leastduring the initial two week treatment cycle, optionally wherein, if thepatient tolerates the initial cycle, the at least one cycle furthercomprises at least one subsequent treatment cycle, each subsequenttreatment cycle comprising at least one administration of theoligoclonal mixture of anti-EGFR antibodies at a third dose. In oneembodiment, the topoisomerase inhibitor is administered during theinitial two week treatment cycle prior to administration of theoligoclonal mixture of anti-EGFR antibodies. In another embodiment, thetopoisomerase inhibitor is additionally administered during the at leastone subsequent treatment cycle, and during each subsequent cycle iscoadministered prior to administration of the oligoclonal mixture ofanti-EGFR antibodies.

In one embodiment, the topoisomerase inhibitor is a topoisomerase Iinhibitor. In one embodiment, the topoisomerase I inhibitor is acamptothecin. In one embodiment, the camptothecin is irinotecan HCl orliposomal irinotecan (e.g., liposomal irinotecan sucrosofate).

In one embodiment, each cycle of the at least one subsequent treatmentcycle is a four week treatment cycle and the third dose of theoligoclonal mixture of anti-EGFR antibodies and the topoisomeraseinhibitor are each administered during day one of week one and day oneof week three of the four week treatment cycle, optionally wherein, ineach cycle of co-administration, the topoisomerase inhibitor isadministered prior to administration of the oligoclonal mixture ofanti-EGFR antibodies. In another embodiment, each cycle of the at leastone subsequent treatment cycle is a four week treatment cycle and thetopoisomerase inhibitor is administered on day one of week one of eachfour week treatment cycle and the anti-EGFR inhibitor is administeredweekly. In one embodiment, in each cycle of co-administration, thetopoisomerase inhibitor is administered prior to administration of theoligoclonal mixture of anti-EGFR antibodies.

In one aspect, provided is a method for ameliorating and/or preventinginfusion reactions in a patient having a cancer comprising administeringto the patient anti-inflammatory treatments prior to administering anoligoclonal mixture of anti-EGFR antibodies and/or irinotecan. Suchmethod comprises a pretreatment comprising an effective amount of eachof 1) drug 1: a histamine H1 blocker; and one or both of: 2) drug 2: ananti-inflammatory steroid; and 3) drug 3: acetaminophen, which isadministered to the patient. In one embodiment, the one or both of 2)and 3) are both of 2) and 3); which pretreatment is administered to thepatient prior to each infusion of the oligoclonal mixture of anti-EGFRantibodies. In another embodiment, the effective amount of each of 1)and one or both of 2) and 3) are all administered to the patient 30-60minutes prior to the administration of the oligoclonal mixture ofanti-EGFR antibodies. In one embodiment, 2) is dexamethasone ormethylprednisolone. In another embodiment, the dexamethasone isadministered to the patient at a dose of 5, 10, 15, 20 or 25 mg, or themethylprednisolone is administered to the patient at a dose of 25, 50,75, 100, or 125 mg. In one embodiment, 2) is methylprednisolone. Inanother embodiment, 1) is diphenhydramine. In another embodiment, thediphenhydramine is administered at a dose of 25 mg to 50 mg. In oneembodiment, the 25 mg to 50 mg is 25 mg or 50 mg.

In one embodiment, if the patient develops an infusion reaction inresponse to a cycle of administration of the oligoclonal mixture ofanti-EGFR antibodies, an effective amount of 1) and/or 2) and/or 3) isre-administered during the cycle. In one embodiment, an effective amountof one or both of 1) and 2) is re-administered when the infusionreaction is observed. In some embodiments, administration of theanti-EGFR antibodies may be interrupted while the effective amount of 2)is re-administered, and then resumed when 2) has been administered. Inanother embodiment, the administration of the pretreatment is repeatedprior to each subsequent cycle.

In various embodiments, treatment of the patient in accordance with thedisclosed methods results in a response classified as PR or CR, or in anSD response.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1A is a graphic representation of the changes in infusion rateassociated with the data set forth in Table III and Table IV plotted incomparison to constant infusion.

FIG. 1B is a graphic representation of the variations in cumulative drug(mg of MM-151) dosed over time for the data set forth in Table III andTable IV plotted in comparison to constant infusion.

FIG. 2A is a graphic representation of the changes in infusion rateassociated with the data set forth in Table V and Table VI for the firstinfusion (“Priming Week 1”) and for the second infusion (“Priming Week2”).

FIG. 2B is a graphic representation of the variations in cumulative drug(mg of MM-151) dosed over time for the data set forth in Table V andTable VI for the first infusion (“Priming Week 1”) and for the secondinfusion (“Priming Week 2”).

FIG. 2C is a graphic representation of the changes in infusion rateassociated with the data set forth in Table V and Table VI for the firstfull dose and for the second full dose (and subsequent full doses).

FIG. 2D is a graphic representation of the variations in cumulative drug(mg of MM-151) dosed over time for the data set forth in Table V andTable VI for the first full dose and for the second full dose (andsubsequent full doses).

FIG. 3 summarizes data from patients that received MM-151 according tothe following regimens: Top row of pie charts: 0.25 to 9 mg/kg MM-151infusion on a standard schedule (no rate optimization or premedication,top line). Middle row of pie charts: 9 mg/kg MM-151 on Modified Schedule1 (slower than usual infusion, middle line). Bottom row of pie charts:data patients treated with MM-151 monotherapy comprising two primingdoses, one of 225 mg and one of 450 mg, followed by two full doses (asopposed to priming doses) of ≧10.5mg/kg on Modified Schedule 2 (withpremedication, bottom line).

FIG. 4 summarizes data from patients that received MM-151 following thegeneration of the data presented in FIG. 3, including 65 patientsincluded in FIGS. 3 and 41 additional patients administered MM-151according to Modified Schedule 2 in the clinical trial. Some of these 41additional patients were administered MM-151 in combination withirinotecan with a MM-151 dose of 4.5, 6, 7.5, or 9 mg/kg (these datawere combined because no effect was seen of irinotecan co-administrationon the frequency or severity of IRRs).

DETAILED DESCRIPTION

Oligoclonal anti-EGFR antibody mixtures represent a recent advance inanti-EGFR cancer therapy. MM-151 and Sym004 (SYMPHOGEN) are eacholigoclonal mixtures of antibodies that bind to the extracellular domainof EGFR and inhibit EGFR activity. MM-151 comprises a formulation in apharmaceutically acceptable carrier of a triple combination of P1X +P2X+P3X at a P1X:P2X:P3X molar ratio of 2:2:1. While MM-151 comprises P1X,P2X and P3X, variants of P1X, P2X and P3X have been prepared thatcomprise V_(H) and V_(L) sequences closely related to those of SEQ IDNOs 1-6; see, e.g., U.S. patent publications Nos. 20110287002 and20140127207. Related variants may preserve a sufficient degree offunctional similarity to provide bioequivalent pharmacokinetics, safetyand efficacy. Closely related variants of P1X V_(H) and V_(L), P2X V_(H)and V_(L), and P3X V_(H) and V_(L) may each include one, two or allthree of the complementarity determining regions (CDRs) of each variableregion. Such variants may be combined (e.g., at a P1X analog:P2Xanalog:P3X analog molar ratio of about 2:2:1 in a pharmaceuticallyacceptable carrier), and, where closely enough related to P1X, P2X andP3X, may thereby form a variant preparation biosimilar to MM-151. Asused in this specification, and in the claims, “MM-151bio” is meant toinclude MM-151 and such MM-151 biosimilar preparations.

Provided herein are methods for treating a cancer with an anti-EGFRantibody therapeutic. In particular, disclosed herein are specificdosages and regimens for administering an oligoclonal anti-EGFR antibodytherapeutic preparation to a human patient having a cancer, such dosagesand regimens being designed to increase a patient's tolerance of thetherapeutic, decrease the likelihood of infusion-related reactions(IRRs), and maximize the amount of dose that may be administered to thepatient safely so at to safely achieve maximum anti-cancer benefits.Previous attempts to mitigate IRR cause by administration ofantibody-based anti-EGFR therapeutics have resulted in very longinfusion times, e.g., 6-9 hours in some cases, depending on body weight.Infusion times longer than 5 hours may be impractical in a clinicalsetting. Other attempts to address infusion reactions require patientsto come to the clinic for treatment two or more days in a row. In orderto avoid these difficulties, a regimen was designed that reduces orprevents infusion reactions, avoids long infusions, and avoids split-daytreatments, thus allowing administration of higher doses of oligoclonalanti-EGFR therapy to patients, which higher doses may provide moreeffective therapy.

Dosage regimens are adjusted to provide the optimum desired response(e.g., a therapeutic response). For example, a single bolus may beadministered, several divided doses may be administered over time or thedose may be proportionally reduced or increased as indicated by theexigencies of the therapeutic situation. For example, human antibodiesmay be administered once or twice weekly by intravenous injection oronce or twice monthly by intravenous injection.

It is especially advantageous to formulate parenteral compositions inunit dosage form for ease of administration and uniformity of dosage.Unit dosage form as used herein refers to physically discrete unitssuited as unitary dosages for the subjects to be treated; each unitcontains a predetermined quantity of antibodies, e.g., a quantitycalculated to provide an amount sufficient for a single cycle ofadministration.

Oligoclonal Antibody Mixtures

P1X is a human IgG1 having a heavy chain variable region (V_(H))comprising SEQ ID NO: 1 and a light chain variable region (V_(L))comprising SEQ ID NO: 2;

P2X is a human IgG1 having a V_(H) comprising SEQ ID NO: 3 and a V_(L)comprising SEQ ID NO: 4; and

P3X is a human IgG1 having a V_(H) comprising SEQ ID NO: 5 and a V_(L)comprising SEQ ID NO: 6.

In various embodiments, P1X, P2X and P3X are each expressed inrecombinant cell protein expression systems. Such protein expressionsystems include commercially available systems using bacterial cells(e.g., E. coli with PET vector), insect cells (e.g., Sf9 cells withpIB/V5-Histadine vector) and mammalian cells (e.g., HEK 293 cells withpLOC vector). A preferred expression host cell is a Chinese hamsterovary (CHO) cell. A preferred expression vector is a commerciallyavailable mammalian expression vector that is suitable for expression ofIgG heavy and light chains in a CHO cell, e.g., one from SELEXIS, LONZA,or GE HEALTHCARE.

TABLE I Exemplary Antibody Variable Regions P1X V_(H)MGFGLSWLFLVAILKGVQCQ SEQ ID NO: 1 VQLVQSGAEVKKPGSSVKVSCKASGGTFSSYAISWVRQAP GQGLEWMGSIIPIFGTVNYA QKFQGRVTITADESTSTAYMELSSLRSEDTAVYYCARDPS VNLYWYFDLWGRGTLVTVSS P1X V_(L) MGTPAQLLFLLLLWLPDTTGSEQ ID NO: 2 DIQMTQSPSTLSASVGDRVT ITCRASQSISSWWAWYQQKPGKAPKLLIYDASSLESGVPS RFSGSGSGTEFTLTISSLQP DDFATYYCQQYHAHPTTFGG GTKVEIKP2X V_(H) MGFGLSWLFLVAILKGVQCQ SEQ ID NO: 3 VQLVQSGAEVKKPGSSVKVSCKASGGTFGSYAISWVRQAP GQGLEWMGSIIPIFGAANPA QKSQGRVTITADESTSTAYMELSSLRSEDTAVYYCAKMGR GKVAFDIWGQGTMVTVSS P2X V_(L) MGTPAQLLFLLLLWLPDTTGSEQ ID NO: 4 DIVMTQSPDSLAVSLGERAT INCKSSQSVLYSPNNKNYLAWYQQKPGQPPKLLIYWASTR ESGVPDRFSGSGSGTDFTLT ISSLQAEDVAVYYCQQYYGSPITFGGGTKVEIK P3X V_(H) MGFGLSWLFLVAILKGVQCQ SEQ ID NO: 5VQLVQSGAEVKKPGASVKVS CKASGYAFTSYGINWVRQAP GQGLEWMGWISAYNGNTYYAQKLRGRVTMTTDTSTSTAYM ELRSLRSDDTAVYYCARDLG GYGSGSVPFDPWGQGTLVTV SSP3X V_(L) MGTPAQLLFLLLLWLPDTTG SEQ ID NO: 6 EIVMTQSPATLSVSPGERATLSCRASQSVSSNLAWYQQKP GQAPRLLIYGASTRATGIPA RFSGSGSGTEFTLTISSLQSEDFAVYYCQDYRTWPRRVFG GGTKVEIK

TABLE II Exemplary Antibody CDRs P1X V_(H)CDR1 SYAIS SEQ ID NO: 7P1X V_(H)CDR2 IIPIFGTVNY SEQ ID NO: 8 P1X V_(H)CDR3 DPSVNL SEQ ID NO: 9P1X V_(L)CDR1 QSISSWWA SEQ ID NO: 10 P1X V_(L)CDR2 DASSL SEQ ID NO: 11P1X V_(L)CDR3 QQYHAHP SEQ ID NO: 12 P2X V_(H)CDR1 SYAIS SEQ ID NO: 13P2X V_(H)CDR2 IIPIFGAANP SEQ ID NO: 14 P2X V_(H)CDR3 MGRGKVSEQ ID NO: 15 P2X V_(L)CDR1 QSVLYSPNNKNYLA SEQ ID NO: 16 P2X V_(L)CDR2WASTR SEQ ID NO: 17 P2X V_(L)CDR3 QQYYGSP SEQ ID NO: 18 P3X V_(H)CDR1SYGIN SEQ ID NO: 19 P3X V_(H)CDR2 ISAYNGNTYY SEQ ID NO: 20 P3X V_(H)CDR3DLGGYGSGS SEQ ID NO: 21 P3X V_(L)CDR1 QSVSSNLA SEQ ID NO: 22P3X V_(L)CDR2 GASTR SEQ ID NO: 23 P3X V_(L)CDR3 QDYRTWPR SEQ ID NO: 24Dosage of Oligoclonal Antibody Mixtures

In one embodiment, the oligoclonal antibody mixture is formulated forintravenous administration. In particular embodiments, the oligoclonalantibody mixture is administered at a dose selected from: priming dosesof from 100 to 1000 mg, e.g., 225 mg or 450 mg, or 3 mg/kg or 6 mg/kg;and full doses of from 1 to 20 mg/kg, e.g., 3 mg/kg, 6 mg/kg, 7.5 mg/kg,9 mg/kg, 10.5 mg/kg, 12 mg/kg, 15 mg/kg or 18 mg/kg or 20 mg/kg. In oneembodiment, the dose of the oligoclonal antibody mixture is varied overtime. For example, the antibody may be initially administered at a lowdose and increased over time.

Camptothecin Topoisomerase I Inhibitors

Irinotecan hydrochloride (HCl) is marketed as CAMPTOSAR® (irinotecanhydrochloride injection). Irinotecan is an antineoplastic agent of thetopoisomerase I inhibitor class that is a derivative of camptothecin, analkaloid extract from plants such as Camptotheca acuminate. Camptothecinand its derivatives are referred to as camptothecins, and irinotecan isa camptothecin. The chemical name for irinotecan is(S)-4,11-diethyl-3,4,12,14-tetrahydro-4-hydroxy-3,14-dioxolH pyrano[3′,4′:6,7]-indolizino[1,2-b]quinolin-9-yl-[1,4′bipiperidine]-1′-carboxylate.Irinotecan HCl is a monohydrochloride trihydrate that is a pale yellowto yellow crystalline powder, with the empirical formulaC₃₃H₃₈N₄O₆.HCl.3H₂O and a molecular weight of 677.19. It is slightlysoluble in water and organic solvents. Irinotecan HCl is also known asCPT-11. Other camptothecin topoisomerase I inhibitors include9-aminocamptothecin, 7-ethylcamptothecin, 10-hydroxycamptothecin,9-nitrocamptothecin, 10,11-methylenedioxycamptothecin,9-amino-10,11-methylenedioxycamptothecin,9-chloro-10,11-methylenedioxycamptothecin, irinotecan, topotecan,lurtotecan, silatecan,(7-(4-methylpiperazinomethylene)-10,11-ethylenedioxy-20(S)-camptothecin,7-(4-methylpiperazinomethylene)-10,11-methylenedioxy-20(S)-camptothecinand 7-(2-N-isopropylamino)ethyl)-(20S)-camptothecin.

Pharmaceutical Compositions

Pharmaceutical compositions suitable for administration to a patient aretypically in forms suitable for parenteral administration, e.g., in aliquid carrier, or suitable for reconstitution into liquid solution orsuspension, for intravenous administration.

In general, compositions typically comprise a pharmaceuticallyacceptable carrier. As used herein, the term “pharmaceuticallyacceptable” means approved by a government regulatory agency or listedin the U.S. Pharmacopeia or another generally recognized pharmacopeiafor use in animals, particularly in humans. The term “carrier” refers toa diluent, adjuvant, excipient, or vehicle with which the antibodies areadministered. Such pharmaceutical carriers can be sterile liquids,typically water and aqueous solutions such as saline and aqueous sucroseor dextrose and glycerol solutions, which may also contain excipientssuch as emulsifiers (e.g., a polysorbate), buffering agents (e.g.phosphate buffers or amino acids). Liquid compositions for parenteraladministration can be formulated for administration by injection orcontinuous infusion. Routes of administration by injection or infusioninclude intravenous, intraperitoneal, intramuscular, intrathecal andsubcutaneous. In one embodiment, an oligoclonal mixture of anti-EGFRantibodies and irinotecan are administered intravenously (e.g.,separately or together, each, e.g., for MM-151, over the course of 60,90, 120, 150, 180, 210, 240, 270, 300, 330, or 360 minutes).

MM-151 may be formulated for intravenous infusion as a clear liquid thatmay be supplied in sterile, single-use vials containing 10 mL of MM-151(with an extractable volume of 9.5 mL) at a total protein concentrationof 25 mg/mL in 20 mM histidine, 10% sucrose, 0.02% polysorbate 80, pH6.0. MM-151 Drug Product thus formulated should be stored at 2-8° C.

Irinotecan HCl is supplied as a sterile, pale yellow, clear, aqueoussolution. It is available in two single-dose sizes in brown glass vials:2 mL-fill vials contain 40 mg irinotecan hydrochloride and 5 mL-fillvials contain 100 mg irinotecan hydrochloride. Irinotecan is alsoavailable in three single-dose sizes in amber-colored polypropyleneCYTOSAFE vials: 2 mL-fill vials contain 40 mg irinotecan hydrochloride,5 mL-fill vials contain 100 mg irinotecan hydrochloride and 15 mL-fillvials contain 300 mg irinotecan hydrochloride. Each milliliter ofsolution contains 20 mg of irinotecan hydrochloride (on the basis of thetrihydrate salt), 45 mg of sorbitol, NF, and 0.9 mg of lactic acid, USP.The pH of the solution has been adjusted to 3.5 (range, 3.0 to 3.8) withsodium hydroxide or hydrochloric acid. Irinotecan is intended fordilution with 5% Dextrose Injection, USP (D5W), or 0.9% Sodium ChlorideInjection, USP, prior to intravenous infusion. The preferred diluent is5% Dextrose Injection, USP.

Patient Populations

Provided herein are effective methods for treating solid tumors (e.g.,that are advanced and/or EGFR dependent) in a human patient using anoligoclonal mixture of anti-EGFR antibodies, or using a combination ofsuch an oligoclonal mixture and irinotecan.

In one embodiment, a human patient for treatment of a cancer inaccordance with the methods provided herein has not been previously beentreated for the cancer with an antineoplastic medication. In anotherembodiment, a human patient for treatment using the subject methods andcompositions has evidence of recurrent or persistent disease followingprimary chemotherapy. In one embodiment, the human patient suffers fromcolorectal cancer, head and neck cancer (e.g., head and neck squamouscell carcinoma), non-small cell lung cancer, gastric cancer, breastcancer, endometrial cancer, ovarian cancer, cervical cancer, bladdercancer (and related urothelial cancers), esophageal cancer, brain cancer(e.g., glioblastoma multiforme) liver cancer (e.g., hepatoma),pancreatic cancer, and squamous cell carcinoma. In one embodiment, thepatient has a pathologically documented, definitively diagnosedcolorectal adenocarcinoma that is locally advanced or metastatic andsurgically unresectable.

In another embodiment, a patient has shown evidence of recurrent orpersistent disease following treatment with at least 1 and no more than2 treatment regimens for locally advanced or metastatic disease. In oneembodiment, if the patient is to receive combination therapy comprisingirinotecan, the patient should have received only 1 prior treatmentcontaining irinotecan.

In one embodiment, patients must have received no prior therapy withEGFR-targeted therapeutics. In another embodiment, patients must havereceived prior therapy with one or more EGFR-targeted therapeutics andhave become refractory to such therapy.

Combination Therapies

The methods provided herein are useful for both anti-EGFR monotherapyand combination therapy with other anti-cancer therapies, e.g.chemotherapeutics (e.g., irinotecan, 5-FU/leucovorin, oxaliplatin (andcombinations of the foregoing such as FOLFOX and FOLFIRI), MM-398 (aloneor in combination with 5-FU/leucovorin), targeted small molecules, e.g.,trametinib, selumetinib, binimetinib, cobimetinib, afatinib, sunitinib,sorafinib, pazopanib, imatinib, vemurafinib, dabrafenib, erlotinib,gefitinib, and lapatinib, or monoclonal antibodies such as seribantumab,MM-141, MM-131, MM-111, ipilimumab, nivolumab, pembrolizumab,pidilizumab, trastuzumab, pertuzumab, ado-trastuzumab emtansine. Each ofthese anti-cancer therapies is preferably co-administered at themanufacturer's recommended dose, unless such a dose causes an adversereaction when administered in combination with MM-151 (or MM-151bio), inwhich case a reduced dose is preferred.

In one embodiment, an oligoclonal mixture of anti-EGFR antibodies isadministered concomitantly with irinotecan, to effect improvement insubjects having a solid tumor. In one embodiment, the oligoclonalmixture of anti-EGFR antibodies is MM-151 or MM-151bio.

As used herein, adjunctive or combined administration(co-administration) includes simultaneous administration of thecompounds in the same or different dosage form, or separateadministration of the compounds (e.g., sequential administration). Forexample, the oligoclonal antibody mixture can be simultaneouslyadministered with irinotecan, wherein both the antibody and theirinotecan are formulated together. Alternatively, the oligoclonalantibody mixture can be administered in combination with irinotecan,wherein both the antibody mixture and the irinotecan are formulated forseparate administration and are administered concurrently orsequentially. For example, the irinotecan can be administered firstfollowed by (e.g., immediately followed by) the administration of theoligoclonal antibody mixture, or vice versa.

Such concurrent or sequential administration beneficially results inboth the oligoclonal antibody mixture and irinotecan beingsimultaneously present in treated patients.

In one embodiment, the oligoclonal antibody mixture is administered as amonotherapy prior to the combination therapy. In another embodiment, theoligoclonal antibody mixture is administered as a monotherapy followingthe combination therapy.

Outcomes

Responses to therapy may include:

Complete Response (CR): Disappearance of all target lesions. Anypathological lymph nodes (whether target or non-target) must havereduction in short axis to <10 mm;

Partial Response (PR): At least a 30% decrease in the sum of thediameters of target lesions, taking as reference the baseline sumdiameters;

Progressive Disease (PD): At least a 20% increase in the sum of thediameters of target lesions, taking as reference the smallest sum onstudy (this includes the baseline sum if that is the smallest on study).In addition to the relative increase of 20%, the sum must alsodemonstrate an absolute increase of at least 5 mm. (Note: the appearanceof one or more new lesions is also considered progression); and

Stable Disease (SD): Neither sufficient shrinkage to qualify for PR norsufficient increase to qualify for PD, taking as reference the smallestsum diameters while on study. A change of 20% or less that does notincrease the sum of the diameters by 5 mm or more is coded as stabledisease. To be assigned a status of stable disease, measurements musthave met the stable disease criteria at least once after study entry ata minimum interval of 6 weeks.

In exemplary outcomes, patients treated according to the methodsdisclosed herein may experience improvement in at least one sign ofcancer. In one embodiment, the patient so treated exhibits CR, PR; inanother embodiment the patient exhibits SD.

In another embodiment, the patient so treated experiences tumorshrinkage and/or decrease in growth rate, i.e., suppression of tumorgrowth. In another embodiment, unwanted cell proliferation is reduced orinhibited. In yet another embodiment, one or more of the following canoccur: the number of cancer cells can be reduced; tumor size can bereduced; cancer cell infiltration into peripheral organs can beinhibited, retarded, slowed, or stopped; tumor metastasis can be slowedor inhibited; tumor growth can be inhibited; recurrence of tumor can beprevented or delayed; one or more of the symptoms associated with cancercan be relieved to some extent.

In other embodiments, such improvement is measured by a reduction in thequantity and/or size of measurable tumor lesions. Measurable lesions aredefined as those that can be accurately measured in at least onedimension (longest diameter is to be recorded) as ≧10 mm by CT scan (CTscan slice thickness no greater than 5 mm), 10 mm caliper measurement byclinical exam or >20 mm by chest X-ray. The size of non-target lesions,e.g., pathological lymph nodes can also be measured for improvement. Inone embodiment, lesions can be measured on chest x-rays or CT or MRIfilms.

In other embodiments, cytology or histology can be used to evaluateresponsiveness to a therapy. The cytological confirmation of theneoplastic origin of any effusion that appears or worsens duringtreatment when the measurable tumor has met criteria for response orstable disease can be considered to differentiate between response orstable disease (an effusion may be a side effect of the treatment) andprogressive disease.

In some embodiments, administration of effective amounts of theoligoclonal anti-EGFR antibody mixture, e.g., MM-151 or MM-151bio, andoptionally irinotecan according to any of the methods provided hereinproduce at least one therapeutic effect selected from the groupconsisting of reduction in size of a tumor, reduction in number ofmetastatic lesions appearing over time, complete remission, partialremission, stable disease, increase in overall response rate, or apathologic complete response. In some embodiments, the provided methodsof combination treatment produce a comparable clinical benefit rate(CBR=CR+PR+SD≧6 months) better than that achieved by the oligoclonalanti-EGFR antibody mixture, e.g., MM-151 or MM-151bio, or irinotecanalone, or the combination of cetuximab and irinotecan. In otherembodiments, the improvement of clinical benefit rate is about 10% 20%,30%, 40%, 50%, 60%, 70%, 80%, 90%, or more compared to cetuximab oririnotecan alone or the combination of cetuximab and irinotecan.

Kits and Unit Dosage Forms

Also provided are kits that include a pharmaceutical compositioncontaining an oligoclonal mixture of anti-EGFR antibodies, such asMM-151 or MM-151bio, and a pharmaceutically-acceptable carrier, in atherapeutically effective amount adapted for use in the precedingmethods.

The kits can optionally also include instructions, e.g., comprisingadministration parameters including dosages and infusion rates, to allowa practitioner (e.g., a physician, nurse, or patient) to administer thecomposition contained therein to a patient having cancer in accordancewith the methods disclosed herein. In one embodiment, the kit furthercomprises irinotecan. Optionally, the kit may comprise a preparation ofoligoclonal anti-EGFR antibodies (e.g., MM-151, MM-151bio or Sym004)and/or irinotecan in a desired unit dosage form for administration.

Pretreatments

Prior to infusion of oligoclonal anti-EGFR antibodies (e.g., 30-60minutes before each infusion), one or more drugs may be administered toreduce the incidence and severity of infusion reactions. A histamine H1antagonist (antihistamine) may be administered. Exemplary antihistaminesfor this pre-treatment include diphenhydramine, chlorpheniramine, andbrompheniramine. In one embodiment, diphenhydramine is administeredorally (p.o.) or intravenously (i.v.) at a dose of 25-50 mg.Acetaminophen may be administered, e.g., at a dose of 650 mg p.o. ori.v. Additionally, an anti-inflammatory steroid may be administered.Exemplary steroids for this purpose include dexamethasone andmethylprednisolone. In one embodiment, methylprednisolone isadministered intravenously (i.v.) at a dose of 25-125 mg (e.g., 25, 50,75, 100, or 125 mg). In another embodiment, dexamethasone isadministered p.o. or i.v. at a dose of 5-25 mg (e.g., 5, 10, 15, 20 or25 mg). Pretreatment may optionally be reduced or discontinued after thefirst full dose (i.e., dose other than a priming dose) of oligoclonalanti-EGFR antibodies, particularly if no infusion reactions areobserved. Pretreatment may optionally be resumed at a later dosingvisit, particularly to reduce the incidence of infusion reactions inpatients that did not receive drug on one or more preceding visits.

EXAMPLES

The present invention is further illustrated by the following Examples,which should not be construed as further limiting. These Examplesincorporate results obtained during a Phase I clinical trial of MM-151.In this trial, patients who received a relatively high dose of MM-151 atthe beginning of the first infusion were much more likely to develop arapidly presenting infusion reaction (e.g., hypersensitivity) at thebeginning of the dosing, requiring a stoppage in treatment, than werepatients who received a relatively lower dose of MM-151. In addition,patients who received higher doses during the first infusion of MM-151and didn't exhibit a hypersensitivity reaction tended to developcytokine-driven infusion reactions about three to six hours after thebeginning of the drug infusion. Finally, patients who receivedanti-inflammatory treatments prior to the first infusion of MM-151exhibited fewer infusion reactions than patients who did not receiveanti-inflammatory treatments prior to MM-151 infusion.

Surprisingly, patients were much less likely to develop an infusionreaction in subsequent infusions compared to the first infusion,indicating that patients experience fewer side effects with eachsubsequent administration of MM-151.

As presented in the tables below “FD” (full dose), may be, e.g., 4.5, 6,7, 7.5, 8, 9, 10, 10.5, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 mg/kg.In those Tables relating to combination therapy comprising irinotecan,“180” indicates 180 mg/m² of irinotecan HCl, which is preferablyadministered prior to MM-151 administration. The amounts of either orboth of 1) each full dose of MM-151 or 2) of each full dose of thecombination therapy, may be reduced during the course of treatment atthe discretion of the treating physician, such as in response to anadverse event.

Example 1 Pre-Treatment

In all patients not treated with the Standard Schedule described below,premedication with methylprednisolone i.v. at a dose of 25-125 mg,diphenhydramine p.o. or i.v. at a dose of 25 or 50 mg, and acetaminophenp.o. or i.v. at a dose of 650 mg is administered to each patient priorto the initial infusion of MM-151 and premedication is preferablycontinued before each subsequent infusion of MM-151, but may be alteredat the treating physician's discretion.

Example 2 A Priming Phase with Escalating Rate of Infusion andSubsequent Dosing for MM-151 Monotherapy Administration

In the following clinical trial, the first 37 patients to be treatedreceived MM-151 according to the Standard Schedule, i.e., by constantinfusion (approximately 60-90 minutes in duration). These patientsfrequently exhibited infusion-related reactions that were sometimessevere. In some cases, administration of MM-151 to patients whoexhibited infusion-related reactions was terminated prematurely and notrestarted (i.e. the intended dose of MM-151 was not administered). Insome cases, patients who exhibited infusion-related reactions werewithdrawn from the trial due to the severity of their reactions. Thetrial design was then modified to enable the determination of whetherMM-151 would be better tolerated with pre-medication and with modifiedinfusion protocols involving administration via a slow first infusion,followed by increased rates on subsequent infusions. Two such modifiedinfusion protocols are set forth below as Modified Schedule 1 andModified Schedule 2.

Administration Details of Modified Schedule 1

In Modified Schedule 1, administration of MM-151 was initiated at a lowinfusion rate for one hour and the rate was then escalated as describedbelow in the following paragraph. Table III below gives an exemplarydosing schedule for patients getting treatment with a full dose ofMM-151 on a weekly basis (QW), every other week (Q2W), or every threeweeks (Q3W). Any pretreatment is given before each administration.Herein, this infusion schedule is termed as “Modified Schedule 1.”

In Modified Schedule 1, the rates of infusion of MM-151 are carefullycontrolled to reduce or prevent hypersensitivity reactions (e.g.,allergic reactions). Modified Schedule 1 is set forth in Table IV below,and provides a rate escalation schedule for the first two infusions atdose level of 10.5 mg/kg to an 85 kg patient. The infusion rate forCycle 1 Week 1 begins at 10 mg/hour (1X) for the first 60 minutesfollowed by an escalation of six subsequent rates for 30 min each—20mg/hour (2X), 40 mg/hour (4X), 60 mg/hour (6X), 100 mg/hour (10X), 150mg/hour (15X), and finally 200 mg/hour (20X). The final 200 mg/hour rateis continued until the full dose is delivered (all of these escalationsteps occurring over the course of approximately seven hours in total).The infusion rate for Cycle 1 Week 2 and subsequent administrationsbegins at 50 mg/hour (5X) for the first 60 minutes followed by anescalation of seven subsequent rates for 30 min each—100 mg/hour (10X),150 mg/hour (15X), 200 mg/hour (20X), 250 mg/hour (25X), 300 mg/hour(30X), 350 mg/hour (35X), and finally 400 mg/hour (40X). The final 200mg/hour rate is continued until the full dose is delivered (all of theseescalation steps occurring over the course of approximately 4.5 hours intotal). If a patient experienced an infusion reaction during aninfusion, the next full dose was optionally (at the treating physician'sdiscretion) administered with the slower Cycle 1 Week 1 schedule. If apatient did not experience an infusion reaction during an infusion, thenext full dose was administered (at the treating physician's discretion)at the faster Cycle 1 Week 2 schedule.

Particular embodiments of this infusion schedule (“Modified Schedule 1”)are shown as line plots in FIGS. 1A-1B. FIG. 1A depicts the rateescalation schedules for Cycle 1 Week 1 and the subsequent full doseadministration(s) and FIG. 1B shows the cumulative amount of drugadministered during these administrations.

TABLE III Dosage and Administration of MM-151 Monotherapy (“ModifiedSchedule 1”) Cycle 1 Subsequent Cycles Schedule W1 W2 W3 W4 W1 W2 W3 W4QW FD FD FD FD FD FD FD FD Q2W FD — FD — FD — FD — Q3W FD — — n/a FD — —n/a

TABLE IV Example of MM-151 administration with an alternative infusionschedule (“Modified Schedule 1”) at 10.5 mg/kg for an 85 kg patientCumulative Rate Drug Drug Cumulative (mg/ Duration Infused Infused TimeInfusion hour) (hr) (mg) (mg) (hr) 1^(st) Infusion 10 1.0 10 10 1.0(Cycle 1 20 0.5 10 20 1.5 Week 1) 40 0.5 20 40 2.0 60 0.5 30 70 2.5 1000.5 50 120 2.0 150 0.5 75 195 3.5 200 3.5 697.5 892.5 7.0 Subsequent 501.0 50 50 1.0 Infusions 100 0.5 50 100 1.5 (Cycle 1 150 0.5 75 175 2.0Week 2, 200 0.5 100 275 2.5 et seq.) 250 0.5 125 400 3.0 300 0.5 150 5503.5 350 0.5 175 725 4.0 400 0.4 167.5 892.5 4.42Administration Details of Modified Schedule 2

Three issues arose during the trial in which Modified Schedule 1 wasemployed. Firstly, the slow infusion schedule required extendedadministration times (administration of the first full dose of MM-151extended to two days for almost all patients). Secondly, the largenumber of rate escalation steps during administration in accordance withModified Schedule 1 created a significant burden for nursing staff,particularly when infusion reactions occurred, as they required ratede-escalation, resulting in highly complex administration patterns.Thirdly, Modified Schedule 1, while reducing the severity of infusionreactions, did not adequately reduce the frequency with which theyoccurred—this is believed to have been due to cytokine mediatedinflammatory events. Modified Schedule 2 was invented to address theseissues.

In Modified Schedule 2, a priming phase designed to enhance the safetyand ease of MM-151 administration precedes Cycle 1. The priming phaseconsists of two weekly fixed doses of 225 mg (Priming Week 1) and 450 mg(Priming Week 2) given prior to Cycle 1. Safety data support the fixed225 mg and 450 mg doses as they equate to approximately 2.7 mg/kg (2.1to 3.7, ±S.D) and approximately 5.4 mg/kg (4.2 to 7.4, ±S.D) for theaverage patient enrolled in this study at the time the clinical trialwas modified to include Modified Schedule 2 (84±23kg (mean ±S.D), range48-169 kg, N=55). Table V below gives an exemplary dosing schedule forpatients getting treatment on a weekly basis (QW), every other week(Q2W), or every three weeks (Q3W). Any pretreatment is given before eachadministration.

In Modified Schedule 2, the rates of infusion of MM-151 are carefullycontrolled to reduce or prevent both hypersensitivity reactions (e.g.,allergic reactions) and cytokine-mediated infusion reactions. Table VIbelow gives a rate escalation schedule for the first four infusions andincludes the Priming Phase and the first two full doses. The infusionrate for Priming Week 1 (W1) begins at 25 mg/hour (1X) for the first 30minutes, followed by a rate of 50 mg/hour (2X) for the second 30minutes, and finally followed by 100 mg/hour (4X) until the full dose isdelivered at slightly less than three hours. The infusion rate forPriming Week 2 (W2) begins at 1X for the first 30 minutes, followed by arate of 2X for the second 30 minutes, followed by the rate of 4X for thenext 30 minutes, and finally by the rate of 8X until the full dose isdelivered at approximately 3 ½ hours. Similarly, the first full dose isadministered at the beginning of Cycle 1 beginning with an infusion rateof 50 mg/hour (2X) for the first 30 minutes, and then advanced at thediscretion of the treating medical professional, for example, followedby a rate of 4X for the next 30 minutes, followed by a rate of 8X forthe next 30 minutes, and finally followed by a rate of 16X until thefull dose is administered to the patient. If a patient experiences aninfusion reaction on one or both Priming Phase infusions, the first fulldose may be administered with a slower schedule beginning with aninfusion rate of 50 mg/hour (2X) for the first 30 minutes, and thenadvanced at the discretion of the treating medical professional, forexample, followed by a rate of 4X for the next 30 minutes, followed by arate of 8X until the full dose is administered to the patient.

Particular embodiments of this infusion schedule (“Modified Schedule 2”)are shown as line plots in FIGS. 2A-2D. FIG. 2A depicts the rateescalation schedules for Priming Week 1 and Priming Week 2. FIG. 2Bshows the cumulative amount of drug administered during Priming Week 1and Priming Week 2. FIG. 2C depicts the rate escalation schedules forCycle 1 Week 1 and the subsequent full dose administration(s) and FIG.2D shows the cumulative amount of drug administered during theseadministrations.

TABLE V Dosage and Administration of MM-151 Monotherapy (“ModifiedSchedule 2”) Priming Phase¹ Cycle 1 Subsequent Cycles Schedule W1 W2 W1W2 W3 W4 W1 W2 W3 W4 QW 225 mg 450 mg FD FD FD FD FD FD FD FD Q2W 225 mg450 mg FD — FD — FD — FD — Q3W 225 mg 450 mg FD — — n/a FD — — n/a ¹DLTevaluation period will consist of both the Priming Phase and cycle 1

TABLE VI MM-151 administration with the optimized infusion schedule(“Modified Schedule 2”) at 10.5 mg/kg for an 85 kg patient CumulativeRate Drug Drug Cumulative (mg/ Time Infused Infused Time Infusion hour)(hr) (mg) (mg) (hr) 1^(st) Infusion 25 0.5 12.5 12.5 0.5 (PrimingWeek 1) 50 0.5 25.0 37.5 1.0 100 1.875 187.5 225.0 2.88 2^(nd) Infusion25 0.5 12.5 12.5 0.5 (Priming Week 2) 50 0.5 25.0 37.5 1.0 100 0.5 50.087.5 1.5 200 1.81 362.5 450 3.31 3^(rd) Infusion 50 0.5 25 25 0.5(1^(st) Full Dose¹) 100 0.5 50 75 1.0 200 0.5 100 175 1.5 400 1.794717.5 892.5 3.29 4^(th) Infusion 100 0.5 50 50 0.5 (2^(nd) Full Dose¹)400 0.5 200 250 1.0 600 1.07 642.5 892.5 2.07 ¹For this embodiment, aFull Dose is 10.5 mg/kg (892.5 mg for an 85 kg patient)Results of Administration of MM-151 by Constant Infusion, “ModifiedSchedule 1” and “Modified Schedule 2”

Results are shown as pie charts in FIG. 3 for patients who wereadministered MM-151 by three infusion schedules—constant infusion over60 to 90 min (“Standard Schedule”), Modified Schedule 1, or ModifiedSchedule 2. As shown in the figure, patients receiving MM-151 viaModified Schedule 1 (middle row) had fewer Grade 3 infusion reactions,but a similar frequency of Grade 2 infusion reactions at the firstvisit, and no infusion reactions at all by the time of the fourth visit,even though these patients received a greater dose of drug (up to 9mg/kg for some patients) than the patients on the Standard Schedule. Asalso shown in the figure, patients receiving MM-151 via ModifiedSchedule 2 (bottom row) had no Grade 3 infusion reactions, had fewerGrade 2 infusion reactions than patients in the other groups at thefirst visit, and no infusion reaction at all by the time of the fourthvisit, even though these patients received a greater dose of drug (up to15 mg/kg for some patients) in the third and fourth administrations thanpatients in the other groups. In FIG. 3, patients who missed a visit butcontinued therapy were recorded as missing for the pie chartcorresponding to the missed visit.

Additional results are shown as pie charts in FIG. 4 and include 41additional patients administered MM-151 according to Modified Schedule 2in the clinical trial following the generation of the data presented inFIG. 3, including patients administered MM-151 in combination withirinotecan. As shown in the figure, patients receiving MM-151 via theoptimized infusion schedule (bottom line) had no Grade 3 infusionreactions and had fewer Grade 2 infusion reactions than patients in theother groups, even though these patients received a greater dose of drug(up to 20 mg/kg for some patients) in the third and fourthadministrations than patients in the other groups. In FIG. 4, patientswho missed a visit but continued therapy were recorded as present forthe next numbered visit, so that the data shown are for the first fouradministrations, regardless of gaps between visits.

Example 3 Dosage and Administration of MM-151+Irinotecan CombinationTherapy (with MM-151 Administered According to “Modified Schedule 2” atWeekly or Biweekly Dosing Intervals)

TABLE VIIa Dosage of MM-151 + Irinotecan Priming Phase¹ Cycle 1Subsequent Cycles W1 W2 W1 W2 W3 W4 W1 W2 W3 W4 MM-151 225 mg 450 mg FDFD FD FD FD FD FD FD Irinotecan 180 — 180 — 180 — 180 — 180 — ¹DLTevaluation period will consist of both the Priming Phase and cycle 1

TABLE VIIb MM-151 + Irinotecan Combination Dose Escalation - Q2W dosing,2 week Priming Phase, Fixed Dosing Priming Phase¹ Cycle 1 SubsequentCycles W1 W2 W1 W2 W3 W4 W1 W2 W3 W4 MM-151 225 mg 450 mg FD — FD — FD —FD — Irinotecan 180 — 180 — 180 — 180 — 180 — ¹DLT Evaluation Period =Priming phase + Cycle 1

Example 4 Alternative Dosing Schedule for MM-151

The following tables highlight alternative MM-151 monotherapy andMM-151+irinotecan infusion schemas. The schedule set forth in Table VIIIis less preferred because it requires multiple days for initialinfusions of MM-151.

TABLE VIII MM-151 Monotherapy Dose Escalation - 2 Day First InfusionCycle n Schedule W 1 W 2 W 3 W 4 QW  D0 - 25-50%¹ FD FD FD D 1 - 50-75%Q2 W D 0 - 25-50% — FD — D 1 - 50-75% ¹D 0 = Day 0 - administer 25-50%of current MM-151 mg/kg dose level; D 1 = Day 1 - administer remainingMM-151 at 50-75% of current dose level; MM-151 administration over 2subsequent days occurs only for the first MM-151 dose in cycle 1

Example 5 Alternative dosing schedules for MM-151 “Modified Schedule 3”

Modified Schedule 3 uses the rate escalation scheme set forth inModified Schedule 2 with dosing set in terms of mg/kg (body weight baseddosing) rather than mg/patient (fixed dose per patient). The 225 mgfixed dose of Modified Schedule 2 is replaced with a 3 mg/kg dose inModified Schedule 3, and the 450 mg fixed dose of Modified Schedule 2 isreplaced with a 6 mg/kg dose in Modified Schedule 3. Following the2-week priming phase, full doses (FD) of MM-151 are administered QW,Q2W, or Q3W as indicated.

TABLE IX MM-151 Monotherapy Dose Escalation - 2 week Priming Phase,mg/kg Dosing Priming Phase¹ Cycle 1 Subsequent Cycles Schedule W1 W2 W1W2 W3 W4 W1 W2 W3 W4 QW 3 6 FD FD FD FD FD FD FD FD Q2W 3 6 FD — FD — FD— FD — Q3W 3 6 FD — — — FD — — — ¹Priming phase only precedes cycle 1;Subsequent cycles have no priming phase; DLT Evaluation Period = Primingphase + Cycle 1

TABLE X MM-151 + Irinotecan Combination Dose Escalation - 2 week PrimingPhase, mg/kg Dosing Priming Phase¹ Cycle 1 Subsequent Cycles W1 W2 W1 W2W3 W4 W1 W2 W3 W4 MM-151 3 6 FD FD FD FD FD FD FD FD Irinotecan 180 —180 — 180 — 180 — 180 — ¹DLT Evaluation Period = Priming phase + Cycle 1

TABLE XI MM-151 + Irinotecan Combination Dose Escalation - Q2W dosing, 2week Priming Phase, mg/kg Dosing Priming Phase¹ Cycle 1 SubsequentCycles W1 W2 W1 W2 W3 W4 W1 W2 W3 W4 MM-151 3 6 FD — FD — FD — FD —Irinotecan 180 — 180 — 180 — 180 — 180 — ¹DLT Evaluation Period =Priming phase + Cycle 1

Example 6 Adjustment of Administration of MM-151 if an Infusion-RelatedReaction Occurs

The following schema highlights the management of infusion reactionsthat may occur during the administration of MM-151. This schemaincorporates the grading of infusion-related reactions as defined by theNational Cancer Institute Common Terminology Criteria for Adverse Events(Version 4.0; as described in the Background above).

If a patient experiences a Grade 1 infusion-related reaction (lowestseverity), the infusion may proceed according to the infusion scheduleand the symptoms should be monitored by the treating physician (or nurseor other medical staff). At the discretion of the treating physician,additional medication may be administered, preferably one or both of ahistamine H1 blocker and an anti-inflammatory steroid.

If a patient experiences a Grade 2 infusion-related reaction (moderateseverity), the infusion of MM-151 should be interrupted and additionalmedication administered, preferably one or both of a histamine H1blocker and an anti-inflammatory steroid. If the infusion-relatedreaction symptoms resolve during the interruption, the infusion may beresumed at a rate equal to or lower than the rate at the time of theinterruption. In one embodiment, the infusion may resume at a rate thatis approximately (or exactly) 50% of the rate at the time of theinterruption. In another embodiment, the infusion rate is initiallylowered and is subsequently escalated, optionally until it reaches orexceeds the rate at the time of the interruption. Preferably, theremaining steps set forth in the infusion rate schedule for the dosingvisit will be carried out to effect the rate escalation.

If a patient experiences a Grade 3 or a Grade 4 infusion-relatedreaction (severe), the infusion of MM-151 should be terminated andadditional medication administered, preferably one or both of ahistamine H1 blocker and an anti-inflammatory steroid. Additionalmedication such as one or both of a bronchodilator and epinephrineshould be administered. The patient should be monitored by the treatingphysician for worsening of symptoms and treated accordingly. If apatient experiences a Grade 3 infusion-related reaction, theadministration of MM-151 may resume at the next scheduled dosing visitat the discretion of the treating physician. If a patient experiences aGrade 4 infusion-related reaction, MM-151 should not be administered tothe patient at any subsequent visit.

An exemplary embodiment of this schema is set forth below and highlightsthe activities that the treating physician may undertake if a patientexhibits an infusion-related reaction. These guidelines may be alteredat the discretion of the treating physician and/or by the guidelines inplace at the medical institution where the administration of MM-151 isbeing performed.

-   If a patient exhibits a Grade 1 infusion-related reaction:    -   Maintain the infusion rate unless progression of symptoms to        ≧Grade 2; if symptoms worsen, refer to the guidelines below.    -   Consider treating the patient with additional medication with        diphenhydramine 25-50 mg p.o. or i.v. and/or methylprednisolone        125 mg (or equivalent) i.v.    -   Monitor the patient every 15 minutes for worsening of condition.-   If a patient exhibits a Grade 2 infusion-related reaction:    -   Interrupt the infusion and, at the discretion of the treating        clinician, disconnect the infusion tubing from the patient.    -   Administer additional medication with diphenhydramine 25-50 mg        p.o. or i.v. and/or methylprednisolone 125 mg (or equivalent)        i.v.    -   Monitor the patient every 15 minutes for worsening of condition        (preferably until symptoms resolve).    -   After recovery from symptoms, resume the infusion rate at 50% of        the previous rate and if no further symptoms appear, increase        rate stepwise until the infusion is completed.    -   If Grade 2 symptoms recur, disconnect the infusion tubing from        patient and do not restart the infusion.    -   If all symptoms have resolved after 7 days, the patient may be        administered MM-151 at the next scheduled dosing visit.    -   If symptoms worsen to ≧Grade 3 at any time, follow the        guidelines below.-   If a patient exhibits a Grade 3 infusion-related reaction:    -   Interrupt the infusion and disconnect the infusion tubing from        the patient.    -   Administer diphenhydramine 25-50 mg i.v.    -   Administer 1) normal saline 2) epinephrine (0.2-0.5 mL of a        1:1000 dilution (0.2-0.5 mg) subcutaneous (s.q.) or        intramuscular (i.m.) and 3) bronchodilators (nebulized albuterol        2.5-5 mg in 3 mL of saline), as medically indicated.    -   Consider additional medication with methylprednisolone 125 mg        (or equivalent) i.v.    -   Monitor the patient every 15 minutes for worsening of condition        (preferably until symptoms resolve).    -   If the symptoms improve and the patient is discharged, advise        patient to seek emergency treatment and notify the treating        clinician if the infusion reaction symptoms recur after        discharge from the clinic.    -   Depending on the severity and persistence of the reaction, the        treating physician may consider administration of MM-151 at the        next scheduled dosing visit.

If a patient exhibits a Grade 4 infusion-related reaction:

-   -   Interrupt the infusion and disconnect the infusion tubing from        the patient.    -   Administer diphenhydramine 50 mg i.v.    -   Administer 1) normal saline 2) epinephrine (0.2-0.5 mL of a        1:1000 dilution (0.2-0.5 mg) s.q. or i.m. and 3) bronchodilators        (nebulized albuterol 2.5-5 mg in 3 mL of saline), as medically        indicated.    -   Consider additional medication with methylprednisolone (or        equivalent) i.v. up to 0.5 mg/kg Q 6 h) to prevent recurrent or        ongoing reactions.    -   Monitor the patient every 15 minutes for worsening of condition        (preferably until symptoms resolve).    -   Consider hospital admission for observation.    -   Do not re-administer MM-151 to the patient.        Equivalents

Those skilled in the art will recognize, or be able to ascertain usingno more than routine experimentation, many equivalents of the specificembodiments described herein. Such equivalents are intended to beencompassed by the following claims. Any combination of the embodimentsdisclosed in the any plurality of the dependent claims or Examples iscontemplated to be within the scope of the disclosure.

Incorporation by Reference

The disclosure of each and every U.S. and foreign patent and pendingpatent application and publication referred to herein is specificallyincorporated herein by reference in its entirety, as are the contents ofSequence Listing and Figures.

What is claimed is:
 1. A method of administering a mixture of threemonoclonal IgG1 anti-EGFR antibodies to a human cancer patient, themethod comprising initially administering the mixture to the patient asa first and a second intravenous infusion over a two week cycle aspriming doses in sequence as set forth in the following table: InfusionInfusion Mixture Cumulative Rate Rate Infused Mixture Infusion Sequence¹(mg/hr) (mg) Infused (mg) 1^(st) Infusion 1^(st) Rate 25 12.5 12.5(Priming Week 1) 2^(nd) Rate 50 25.0 37.5 3^(rd) Rate 100 187.5 225.02^(nd) Infusion 1^(st) Rate 25 12.5 12.5 (Priming Week 2) 2^(nd) Rate 5025.0 37.5 3^(rd) Rate 100 50.0 87.5 4^(th) Rate 200 362.5 450 ¹perinfusion

wherein the 1^(st) infusion of the mixture is administered during thepriming week 1 at the 1^(st) rate for a 1/2 hour, immediately followedby the 2^(nd) rate for a second 1/2 hour, immediately followed by the3^(rd) rate until all of the first dose and 225 mg of mixture has beenadministered; wherein the 2^(nd) infusion of the mixture is administeredduring priming week 2 at the 1^(st) rate for a 1/2 hour, immediatelyfollowed by the 2^(nd) rate for the second 1/2 hour, immediatelyfollowed by the 3^(rd) rate for a 1/2 hour, immediately followed by the4^(th) rate until all of the first dose and 450 mg of mixture has beenadministered; wherein, prior to each infusion of the mixture ofanti-EGFR antibodies, diphenhydramine is administered to the patientorally or intravenously at a dose of 25 mg-50 mg and methylprednisoloneis administered to the patient intravenously at a dose of 25-125 mg; andwherein the mixture comprises: i) a first monoclonal antibody comprisingheavy chain CDRs 1, 2 and 3 set forth in SEQ ID NOs: 7, 8 and 9respectively, and light chain CDRs 1, 2 and 3 set forth in SEQ ID NOs:10, 11 and 12 respectively; ii) a second monoclonal antibody comprisingheavy chain CDRs 1, 2 and 3 set forth in SEQ ID NOs: 13, 14 and 15respectively and light chain CDRs 1, 2 and 3 set forth in SEQ ID NOs:16, 17, and 18 respectively; and iii) a third monoclonal antibodycomprising heavy chain CDRs 1, 2 and 3 set forth in SEQ ID NOs: 19, 20and 21 respectively, and light chain CDRs 1, 2 and 3 set forth in SEQ IDNOs: 22, 23 and 24 respectively; wherein the first antibody, the secondantibody, and the third antibody are formulated in a mixture at a molarratio to each other of 2:2:1, respectively; wherein the mixture of threemonoclonal IgG1 anti-EGFR antibodies is administered to a human cancerpatient diagnosed with colorectal cancer, in combination with liposomalirinotecan.
 2. The method of claim 1, wherein the dose ofmethylprednisolone is 125 mg.
 3. The method of claim 1, wherein thefirst antibody comprises a heavy chain variable region comprising SEQ IDNO:1 and a light chain variable region comprising SEQ ID NO:2, thesecond antibody comprises a heavy chain variable region comprising SEQID NO:3 and a light chain variable region comprising SEQ ID NO:4; andthe third antibody comprises a heavy chain variable region comprisingSEQ ID NO:5 and a light chain variable region comprising SEQ ID NO:6. 4.The method of claim 1, wherein, prior to each infusion of the mixture ofanti-EGFR antibodies, acetaminophen is administered to the patient at adose of 650 mg.
 5. The method of claim 1, wherein the mixture of threemonoclonal IgG1 anti-EGFR antibodies is MM-151.
 6. The method of claim1, wherein the mixture of three monoclonal IgG1 anti-EGFR antibodies isadministered in further combination with 5-fluorouracil and leucovorin.